Sarcopenia, the association of decreased muscle mass and function, is commonly seen in the elderly and it is also a serious complication of many chronic diseases such as cancer, obstructive lung disease and heart failure. This is of significant concern because sarcopenia is associated with poor functionality, impaired ability to perform activities of daily living, loss of independence and increased mortality. There are currently no available treatments for this condition despite the significant burden that sarcopenia represents to the elderly. Several mechanisms are involved in the development of sarcopenia including decreased protein synthesis, increased proteolysis and inflammation through nuclear factor ?B (NF?B)-dependent pathways. Emerging evidence suggests that the hormone ghrelin regulates these and other pathways affecting muscle mass. However, ghrelin's effects on muscle mass and function and the mechanisms mediating its effects in the setting of sarcopenia of aging are not known. The long-term objectives of this application are to establish the mechanisms mediating the action of ghrelin and the ghrelin receptor GHSR1a in sarcopenia of aging. We hypothesize that ghrelin prevents aging-associated sarcopenia by: a) Increasing protein synthesis and decreasing proteolysis, b) downregulating inflammation and NF?B activation, and c) that these effects are at least partially mediated through the ghrelin receptor GHSR1a. Our specific aims are to determine the role of ghrelin and the GHSR1a in regulating muscle mass and function in this setting. Using our model of aging-associated sarcopenia, we will: 1) Establish the extent to which muscle mass, muscle performance, protein synthesis and proteolysis are regulated by ghrelin, 2) Characterize the role of ghrelin in modulating inflammation and NF?B activation during aging, and 3) Determine the role of the ghrelin receptor GHSR1a in this setting. Design and methods: We will characterize the role of ghrelin and the GHSR-1a by establishing our recently developed model of sarcopenia of aging in the background of ghrelin and GHSR-1a wild type and KO animals. Furthermore, we will establish the role of inflammation and NF?B activity by exploiting a transgenic mouse line that has been engineered to express luciferase and green fluorescent protein under control of a promoter that contains NF?B consensus binding sites. In-vitro studies will also be performed to further characterize the mechanisms mediating ghrelin's action. Significance: The present proposal will establish the role of ghrelin and the GHSR1a in the setting of sarcopenia of aging, opening new avenues for its treatment. An improvement in functional performance would allow individuals to stay home longer, decreasing hospitalizations, improving quality of life and reducing healthcare costs. It is possible that improving these outcomes will increase longevity. PUBLIC HEALTH RELEVANCE: The loss of muscle mass and function known as sarcopenia is very common in the elderly, reducing functionality and quality of life, and increasing mortality. The novel hormone ghrelin may prevent the development of sarcopenia and this proposal will determine its effects and mechanisms of action in this setting. The results generated by these studies will help us to develop treatments for sarcopenia;thereby improving quality of life by allowing patients to stay home longer, decreasing the need for hospitalizations and reducing the cost of healthcare.